Translational Neuroscience

, Volume 4, Issue 4, pp 385–409 | Cite as

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

  • Aida Attar
  • Farid Rahimi
  • Gal Bitan
Review Article


Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no disease-modifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies — the green-tea derivative (−)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01’s effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.


Amyloid Amyloidosis Alzheimer’s disease Parkinson’s disease Inhibitor Molecular tweezers Polyphenol 



Alzheimer’s disease


Atomic force microscopy

Amyloid beta


Amyloid β-protein precursor



CYP 450

Cytochrome P450










Electron microscopy


Familial amyloidotic polyneuropathy


Islet amyloid polypeptide


Half maximal inhibitory concentration




1 - Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine


Molecular tweezer


3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide




Nuclear magnetic resonance


Parkinson’s disease


Sodium dodecyl sulfate polyacrylamide gel electrophoresis


Surface plasmon resonance imaging


Thioflavin T




Ubiquitin-proteasome system


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. [1]
    Rahimi F., Shanmugam A., Bitan G., Structure-function relationships of pre-fibrillar protein assemblies in Alzheimer’s disease and related disorders, Curr. Alzheimer Res., 2008, 5, 319–341PubMedCentralPubMedGoogle Scholar
  2. [2]
    Fändrich M., Oligomeric intermediates in amyloid formation: structure determination and mechanisms of toxicity, J. Mol. Biol., 2012, 421, 427–440PubMedGoogle Scholar
  3. [3]
    Serpell L.C., Alzheimer’s amyloid fibrils: structure and assembly, Biochim. Biophys. Acta, 2000, 1502, 16–30PubMedGoogle Scholar
  4. [4]
    Vinters H.V., Tung S., Solis O.E., Pathologic Lesions in Alzheimer disease and Other Neurodegenerative Diseases—Cellular and Molecular Components, In: Rahimi F., Bitan G. (Eds.), Non-fibrillar Amyloidogenic Protein Assemblies—Common Cytotoxins Underlying Degenerative Diseases, Springer, 2012Google Scholar
  5. [5]
    Hardy J.A., Higgins G.A., Alzheimer’s disease: the amyloid cascade hypothesis, Science, 1992, 256, 184–185PubMedGoogle Scholar
  6. [6]
    Soto C., Estrada L., Amyloid inhibitors and β-sheet breakers, Subcell. Biochem., 2005, 38, 351–364PubMedGoogle Scholar
  7. [7]
    Necula M., Kayed R., Milton S., Glabe C.G., Small molecule inhibitors of aggregation indicate that amyloid β oligomerization and fibrillization pathways are independent and distinct, J. Biol. Chem., 2007, 282, 10311–10324PubMedGoogle Scholar
  8. [8]
    Ladiwala A.R., Dordick J.S., Tessier P.M., Aromatic small molecules remodel toxic soluble oligomers of amyloid β through three independent pathways, J. Biol. Chem., 2011, 286, 3209–3218PubMedGoogle Scholar
  9. [9]
    Liu T., Bitan G., Modulating self-assembly of amyloidogenic proteins as a therapeutic approach for neurodegenerative diseases: strategies and mechanisms, ChemMedChem, 2012, 7, 359–374PubMedGoogle Scholar
  10. [10]
    Jan A., Adolfsson O., Allaman I., Buccarello A.L., Magistretti P.J., Pfeifer A., et al., Aβ42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Aβ42 species, J. Biol. Chem., 2011, 286, 8585–8596PubMedGoogle Scholar
  11. [11]
    Eikelenboom P., Veerhuis R., Familian A., Hoozemans J.J., van Gool W.A., Rozemuller A.J., Neuroinflammation in plaque and vascular β-amyloid disorders: clinical and therapeutic implications, Neurodegener. Dis., 2008, 5, 190–193PubMedGoogle Scholar
  12. [12]
    Esteras-Chopo A., Pastor M.T., Serrano L., Lopez de la Paz M., New strategy for the generation of specific D-peptide amyloid inhibitors, J. Mol. Biol., 2008, 377, 1372–1381PubMedGoogle Scholar
  13. [13]
    Fradinger E.A., Monien B.H., Urbanc B., Lomakin A., Tan M., Li H., et al., C-terminal peptides coassemble into Aβ42 oligomers and protect neurons against Aβ42-induced neurotoxicity, Proc. Natl. Acad. Sci. USA, 2008, 105, 14175–14180PubMedGoogle Scholar
  14. [14]
    Doig A.J., Peptide inhibitors of β-amyloid aggregation, Curr. Opin. Drug Discov. Devel., 2007, 10, 533–539PubMedGoogle Scholar
  15. [15]
    Cheng P.N., Liu C., Zhao M., Eisenberg D., Nowick J.S., Amyloid β-sheet mimics that antagonize protein aggregation and reduce amyloid toxicity, Nat. Chem., 2012, 4, 927–933PubMedCentralPubMedGoogle Scholar
  16. [16]
    van Groen T., Wiesehan K., Funke S.A., Kadish I., Nagel-Steger L., Willbold D., Reduction of Alzheimer’s disease amyloid plaque load in transgenic mice by D3, A D-enantiomeric peptide identified by mirror image phage display, ChemMedChem, 2008, 3, 1848–1852PubMedGoogle Scholar
  17. [17]
    Belluti F., Rampa A., Gobbi S., Bisi A., Small-molecule inhibitors/modulators of amyloid-β peptide aggregation and toxicity for the treatment of Alzheimer’s disease—A patent review (2010–2012), Expert Opin. Ther. Pat., 2013Google Scholar
  18. [18]
    Re F., Airoldi C., Zona C., Masserini M., La Ferla B., Quattrocchi N., et al., β amyloid aggregation inhibitors: small molecules as candidate drugs for therapy of Alzheimer’s disease, Curr. Med. Chem., 2010, 17, 2990–3006PubMedGoogle Scholar
  19. [19]
    Roberts B.E., Shorter J., Escaping amyloid fate, Nat. Struct. Mol. Biol., 2008, 15, 544–546PubMedGoogle Scholar
  20. [20]
    Wang W., Protein aggregation and its inhibition in biopharmaceutics, Int. J. Pharm., 2005, 289, 1–30PubMedGoogle Scholar
  21. [21]
    Bartolini M., Andrisano V., Strategies for the inhibition of protein aggregation in human diseases, ChemBioChem., 2010, 11, 1018–1035PubMedGoogle Scholar
  22. [22]
    Bose M., Gestwicki J.E., Devasthali V., Crabtree G.R., Graef I.A., ‘Natureinspired’ drug-protein complexes as inhibitors of Aβ aggregation, Biochem. Soc. Trans., 2005, 33, 543–547PubMedGoogle Scholar
  23. [23]
    Cole G.M., Teter B., Frautschy S.A., Neuroprotective effects of curcumin, Adv. Exp. Med. Biol., 2007, 595, 197–212PubMedCentralPubMedGoogle Scholar
  24. [24]
    Bastianetto S., Krantic S., Quirion R., Polyphenols as potential inhibitors of amyloid aggregation and toxicity: possible significance to Alzheimer’s disease, Mini Rev. Med. Chem., 2008, 8, 429–435PubMedGoogle Scholar
  25. [25]
    Porat Y., Abramowitz A., Gazit E., Inhibition of amyloid fibril formation by polyphenols: structural similarity and aromatic interactions as a common inhibition mechanism, Chem. Biol. Drug Des., 2006, 67, 27–37PubMedGoogle Scholar
  26. [26]
    Mandel S.A., Amit T., Weinreb O., Reznichenko L., Youdim M.B., Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases, CNS Neurosci. Ther., 2008, 14, 352–365PubMedGoogle Scholar
  27. [27]
    Albani D., Polito L., Signorini A., Forloni G., Neuroprotective properties of resveratrol in different neurodegenerative disorders, BioFactors, 2010, 36, 370–376PubMedGoogle Scholar
  28. [28]
    Cheng B., Liu X., Gong H., Huang L., Chen H., Zhang X., et al., Coffee components inhibit amyloid formation of human islet amyloid polypeptide in vitro: possible link between coffee consumption and diabetes mellitus, J. Agric. Food Chem., 2011, 59, 13147–13155PubMedGoogle Scholar
  29. [29]
    Huang Y., Jin M., Pi R., Zhang J., Chen M., Ouyang Y., et al., Protective effects of caffeic acid and caffeic acid phenethyl ester against acrolein-induced neurotoxicity in HT22 mouse hippocampal cells, Neurosci. Lett., 2013, 535, 146–151PubMedGoogle Scholar
  30. [30]
    Mohamed T., Yeung J.C., Vasefi M.S., Beazely M.A., Rao P.P., Development and evaluation of multifunctional agents for potential treatment of Alzheimer’s disease: application to a pyrimidine-2,4-diamine template, Bioorg. Med. Chem. Lett., 2012, 22, 4707–4712PubMedGoogle Scholar
  31. [31]
    Mao F., Huang L., Luo Z., Liu A., Lu C., Xie Z., et al., O-Hydroxyl-or o-amino benzylamine-tacrine hybrids: multifunctional biometals chelators, antioxidants, and inhibitors of cholinesterase activity and amyloid-β aggregation, Bioorg. Med. Chem., 2012, 20, 5884–5892PubMedGoogle Scholar
  32. [32]
    Pi R., Mao X., Chao X., Cheng Z., Liu M., Duan X., et al., Tacrine-6-ferulic acid, a novel multifunctional dimer, inhibits amyloid-β-mediated Alzheimer’s disease-associated pathogenesis in vitro and in vivo, PLoS One, 2012, 7, e31921PubMedCentralPubMedGoogle Scholar
  33. [33]
    Bag S., Ghosh S., Tulsan R., Sood A., Zhou W., Schifone C., et al., Design, synthesis and biological activity of multifunctional α,β-unsaturated carbonyl scaffolds for Alzheimer’s disease, Bioorg. Med. Chem. Lett., 2013Google Scholar
  34. [34]
    Nunes A., Marques S.M., Quintanova C., Silva D.F., Cardoso S.M., Chaves S., et al., Multifunctional iron-chelators with protective roles against neurodegenerative diseases, Dalton Trans., 2013Google Scholar
  35. [35]
    Telpoukhovskaia M.A., Patrick B.O., Rodriguez-Rodriguez C., Orvig C., Exploring the multifunctionality of thioflavin- and deferiprone-based molecules as acetylcholinesterase inhibitors for potential application in Alzheimer’s disease, Mol. Biosyst., 2013, 9, 792–805PubMedGoogle Scholar
  36. [36]
    Török B., Sood A., Bag S., Tulsan R., Ghosh S., Borkin D., et al., Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly, Biochemistry, 2013, 52, 1137–1148PubMedGoogle Scholar
  37. [37]
    Granzotto A., Zatta P., Resveratrol acts not through anti-aggregative pathways but mainly via its scavenging properties against Aβ and Aβ-metal complexes toxicity, PLoS One, 2011, 6, e21565PubMedCentralPubMedGoogle Scholar
  38. [38]
    Stratton S.P., Bangert J.L., Alberts D.S., Dorr R.T., Dermal toxicity of topical (−)epigallocatechin-3-gallate in BALB/c and SKH1 mice, Cancer Lett., 2000, 158, 47–52PubMedGoogle Scholar
  39. [39]
    Miyamoto Y., Haylor J.L., El Nahas A.M., Cellular toxicity of catechin analogues containing gallate in opossum kidney proximal tubular (OK) cells, J. Toxicol. Sci., 2004, 29, 47–52PubMedGoogle Scholar
  40. [40]
    Mak J.C., Potential role of green tea catechins in various disease therapies: progress and promise, Clin. Exp. Pharmacol. Physiol., 2012, 39, 265–273PubMedGoogle Scholar
  41. [41]
    Balentine D.A., Wiseman S.A., Bouwens L.C., The chemistry of tea flavonoids, Crit. Rev. Food Sci. Nutr., 1997, 37, 693–704PubMedGoogle Scholar
  42. [42]
    Khan N., Afaq F., Saleem M., Ahmad N., Mukhtar H., Targeting multiple signaling pathways by green tea polyphenol (−)-epigallocatechin-3-gallate, Cancer Res., 2006, 66, 2500–2505PubMedGoogle Scholar
  43. [43]
    Ehrnhoefer D.E., Duennwald M., Markovic P., Wacker J.L., Engemann S., Roark M., et al., Green tea (−)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington’s disease models, Hum. Mol. Genet., 2006, 15, 2743–2751PubMedGoogle Scholar
  44. [44]
    Barranco Quintana J.L., Allam M.F., Del Castillo A.S., Navajas R.F., Parkinson’s disease and tea: a quantitative review, J. Am. Coll. Nutr., 2009, 28, 1–6PubMedGoogle Scholar
  45. [45]
    Hellenbrand W., Seidler A., Boeing H., Robra B.P., Vieregge P., Nischan P., et al., Diet and Parkinson’s disease. I: A possible role for the past intake of specific foods and food groups. Results from a selfadministered food-frequency questionnaire in a case-control study, Neurology, 1996, 47, 636–643PubMedGoogle Scholar
  46. [46]
    Ng T.P., Feng L., Niti M., Kua E.H., Yap K.B., Tea consumption and cognitive impairment and decline in older Chinese adults, Am. J. Clin. Nutr., 2008, 88, 224–231PubMedGoogle Scholar
  47. [47]
    Dragicevic N., Smith A., Lin X., Yuan F., Copes N., Delic V., et al., Green tea epigallocatechin-3-gallate (EGCG) and other flavonoids reduce Alzheimer’s amyloid-induced mitochondrial dysfunction, J. Alzheimers Dis., 2011, 26, 507–521PubMedGoogle Scholar
  48. [48]
    Fernandez J.W., Rezai-Zadeh K., Obregon D., Tan J., EGCG functions through estrogen receptor-mediated activation of ADAM10 in the promotion of non-amyloidogenic processing of APP, FEBS Lett., 2010, 584, 4259–4267PubMedCentralPubMedGoogle Scholar
  49. [49]
    Lin C.L., Chen T.F., Chiu M.J., Way T.D., Lin J.K., Epigallocatechin gallate (EGCG) suppresses β-amyloid-induced neurotoxicity through inhibiting c-Abl/FE65 nuclear translocation and GSK3 β activation, Neurobiol. Aging, 2009, 30, 81–92PubMedGoogle Scholar
  50. [50]
    Mandel S.A., Amit T., Kalfon L., Reznichenko L., Weinreb O., Youdim M.B., Cell signaling pathways and iron chelation in the neurorestorative activity of green tea polyphenols: special reference to epigallocatechin gallate (EGCG), J. Alzheimers Dis., 2008, 15, 211–222PubMedGoogle Scholar
  51. [51]
    Singh B.N., Shankar S., Srivastava R.K., Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications, Biochem. Pharmacol., 2011, 82, 1807–1821PubMedGoogle Scholar
  52. [52]
    Smith A., Giunta B., Bickford P.C., Fountain M., Tan J., Shytle R.D., Nanolipidic particles improve the bioavailability and α-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer’s disease, Int. J. Pharm., 2010, 389, 207–212PubMedGoogle Scholar
  53. [53]
    Ruidavets J., Teissedre P., Ferrieres J., Carando S., Bougard G., Cabanis J., Catechin in the Mediterranean diet: vegetable, fruit or wine?, Atherosclerosis, 2000, 153, 107–117PubMedGoogle Scholar
  54. [54]
    Chyu K.Y., Babbidge S.M., Zhao X., Dandillaya R., Rietveld A.G., Yano J., et al., Differential effects of green tea-derived catechin on developing versus established atherosclerosis in apolipoprotein E-null mice, Circulation, 2004, 109, 2448–2453PubMedGoogle Scholar
  55. [55]
    Katiyar S., Elmets C.A., Katiyar S.K., Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair, J. Nutr. Biochem., 2007, 18, 287–296PubMedGoogle Scholar
  56. [56]
    Meng F., Abedini A., Plesner A., Verchere C.B., Raleigh D.P., The flavanol (−)-epigallocatechin 3-gallate inhibits amyloid formation by islet amyloid polypeptide, disaggregates amyloid fibrils, and protects cultured cells against IAPP-induced toxicity, Biochemistry, 2010, 49, 8127–8133PubMedCentralPubMedGoogle Scholar
  57. [57]
    Ehrnhoefer D.E., Bieschke J., Boeddrich A., Herbst M., Masino L., Lurz R., et al., EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers, Nat. Struct. Mol. Biol., 2008, 15, 558–566PubMedGoogle Scholar
  58. [58]
    Bieschke J., Russ J., Friedrich R.P., Ehrnhoefer D.E., Wobst H., Neugebauer K., et al., EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity, Proc. Natl. Acad. Sci. USA, 2010, 107, 7710–7715PubMedGoogle Scholar
  59. [59]
    Masuda M., Suzuki N., Taniguchi S., Oikawa T., Nonaka T., Iwatsubo T., et al., Small molecule inhibitors of α-synuclein filament assembly, Biochemistry, 2006, 45, 6085–6094PubMedGoogle Scholar
  60. [60]
    Hauber I., Hohenberg H., Holstermann B., Hunstein W., Hauber J., The main green tea polyphenol epigallocatechin-3-gallate counteracts semen-mediated enhancement of HIV infection, Proc. Natl. Acad. Sci. USA, 2009, 106, 9033–9038PubMedGoogle Scholar
  61. [61]
    Popovych N., Brender J.R., Soong R., Vivekanandan S., Hartman K., Basrur V., et al., Site specific interaction of the polyphenol EGCG with the SEVI amyloid precursor peptide PAP(248–286), J. Phys. Chem. B, 2012, 116, 3650–3658PubMedCentralPubMedGoogle Scholar
  62. [62]
    Chandrashekaran I.R., Adda C.G., MacRaild C.A., Anders R.F., Norton R.S., Inhibition by flavonoids of amyloid-like fibril formation by Plasmodium falciparum merozoite surface protein 2, Biochemistry, 2010, 49, 5899–5908PubMedGoogle Scholar
  63. [63]
    Chandrashekaran I.R., Adda C.G., Macraild C.A., Anders R.F., Norton R.S., EGCG disaggregates amyloid-like fibrils formed by Plasmodium falciparum merozoite surface protein 2, Arch. Biochem. Biophys., 2011, 513, 153–157PubMedCentralPubMedGoogle Scholar
  64. [64]
    Rambold A.S., Miesbauer M., Olschewski D., Seidel R., Riemer C., Smale L., et al., Green tea extracts interfere with the stress-protective activity of PrP and the formation of PrP, J. Neurochem., 2008, 107, 218–229PubMedGoogle Scholar
  65. [65]
    Attar A., Bitan G., Disrupting Self-Assembly and Toxicity of Amyloidogenic Protein Oligomers by “Molecular Tweezers”-from the Test Tube to Animal Models, Curr. Pharm. Des., 2013, In pressGoogle Scholar
  66. [66]
    Klärner F.G., Schrader T., Aromatic interactions by molecular tweezers and clips in chemical and biological systems, Acc. Chem. Res., 2013, 46, 967–978PubMedGoogle Scholar
  67. [67]
    Fokkens M., Schrader T., Klärner F.G., A molecular tweezer for lysine and arginine, J. Am. Chem. Soc., 2005, 127, 14415–14421PubMedGoogle Scholar
  68. [68]
    Talbiersky P., Bastkowski F., Klärner F.G., Schrader T., Molecular clip and tweezer introduce new mechanisms of enzyme inhibition, J. Am. Chem. Soc., 2008, 130, 9824–9828PubMedGoogle Scholar
  69. [69]
    Sinha S., Lopes D.H., Du Z., Pang E.S., Shanmugam A., Lomakin A., et al., Lysine-specific molecular tweezers are broad-spectrum inhibitors of assembly and toxicity of amyloid proteins, J. Am. Chem. Soc., 2011, 133, 16958–16969PubMedCentralPubMedGoogle Scholar
  70. [70]
    Bier D., Rose R., Bravo-Rodriguez K., Bartel M., Ramirez-Anguita J.M., Dutt S., et al., Molecular tweezers modulate 14-3-3 protein-protein interactions, Nat. Chem., 2013, 5, 234–239PubMedGoogle Scholar
  71. [71]
    Attar A., Ripoli C., Riccardi E., Maiti P., Li Puma D.D., Liu T., et al., Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers, Brain, 2012, 135, 3735–3748PubMedGoogle Scholar
  72. [72]
    Prabhudesai S., Sinha S., Attar A., Kotagiri A., Fitzmaurice A.G., Lakshmanan R., et al., A novel “molecular tweezer” inhibitor of α-synuclein neurotoxicity in vitro and in vivo, Neurotherapeutics, 2012, 9, 464–476PubMedGoogle Scholar
  73. [73]
    Glenner G.G., Wong C.W., Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein, Biochem. Biophys. Res. Commun., 1984, 120, 885–890PubMedGoogle Scholar
  74. [74]
    Masters C.L., Simms G., Weinman N.A., Multhaup G., McDonald B.L., Beyreuther K., Amyloid plaque core protein in Alzheimer disease and Down syndrome, Proc. Natl. Acad. Sci. U.S.A., 1985, 82, 4245–4249PubMedCentralPubMedGoogle Scholar
  75. [75]
    Hardy J., Selkoe D.J., The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics, Science, 2002, 297, 353–356.PubMedGoogle Scholar
  76. [76]
    Bastianetto S., Yao Z.X., Papadopoulos V., Quirion R., Neuroprotective effects of green and black teas and their catechin gallate esters against β-amyloid-induced toxicity, Eur. J. Neurosci., 2006, 23, 55–64PubMedGoogle Scholar
  77. [77]
    LeVine H., 3rd, Quantification of β-sheet amyloid fibril structures with thioflavin T., Methods Enzymol., 1999, 309, 274–284PubMedGoogle Scholar
  78. [78]
    Palhano F.L., Lee J., Grimster N.P., Kelly J.W., Toward the molecular mechanism(s) by which EGCG treatment remodels mature amyloid fibrils, J. Am. Chem. Soc., 2013, 135, 7503–7510PubMedGoogle Scholar
  79. [79]
    Walsh D.M., Klyubin I., Fadeeva J.V., Cullen W.K., Anwyl R., Wolfe M.S., et al., Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo, Nature, 2002, 416, 535–539PubMedGoogle Scholar
  80. [80]
    Reed M.N., Hofmeister J.J., Jungbauer L., Welzel A.T., Yu C., Sherman M.A., et al., Cognitive effects of cell-derived and synthetically derived Aβ oligomers, Neurobiol. Aging, 2011, 32, 1784–1794PubMedCentralPubMedGoogle Scholar
  81. [81]
    O’Nuallain B., Freir D.B., Nicoll A.J., Risse E., Ferguson N., Herron C.E., et al., Amyloid β-protein dimers rapidly form stable synaptotoxic protofibrils, J. Neurosci., 2010, 30, 14411–14419PubMedCentralPubMedGoogle Scholar
  82. [82]
    Kayed R., Head E., Thompson J.L., McIntire T.M., Milton S.C., Cotman C.W., et al., Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis, Science, 2003, 300, 486–489PubMedGoogle Scholar
  83. [83]
    Paz M.A., Flückiger R., Boak A., Kagan H.M., Gallop P.M., Specific detection of quinoproteins by redox-cycling staining, J. Biol. Chem., 1991, 266, 689–692PubMedGoogle Scholar
  84. [84]
    Lopez del Amo J.M., Fink U., Dasari M., Grelle G., Wanker E.E., Bieschke J., et al., Structural properties of EGCG-induced, nontoxic Alzheimer’s disease Aβ oligomers, J. Mol. Biol., 2012, 421, 517–524PubMedGoogle Scholar
  85. [85]
    Bitan G., Kirkitadze M.D., Lomakin A., Vollers S.S., Benedek G.B., Teplow D.B., Amyloid β-protein (Aβ) assembly: Aβ40 and Aβ42 oligomerize through distinct pathways, Proc. Natl. Acad. Sci. USA, 2003, 100, 330–335PubMedGoogle Scholar
  86. [86]
    Hoshi M., Sato M., Matsumoto S., Noguchi A., Yasutake K., Yoshida N., et al., Spherical aggregates of β-amyloid (amylospheroid) show high neurotoxicity and activate tau protein kinase I/glycogen synthase kinase-3β, Proc. Natl. Acad. Sci. USA, 2003, 100, 6370–6375PubMedGoogle Scholar
  87. [87]
    Dahlgren K.N., Manelli A.M., Stine W.B., Jr., Baker L.K., Krafft G.A., LaDu M.J., Oligomeric and fibrillar species of amyloid-β peptides differentially affect neuronal viability, J. Biol. Chem., 2002, 277, 32046–32053PubMedGoogle Scholar
  88. [88]
    Harper J.D., Lansbury P.T., Jr., Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins, Annu. Rev. Biochem, 1997, 66, 385–407PubMedGoogle Scholar
  89. [89]
    Petkova A.T., Ishii Y., Balbach J.J., Antzutkin O.N., Leapman R.D., Delaglio F., et al., A structural model for Alzheimer’s β-amyloid fibrils based on experimental constraints from solid state NMR, Proc. Natl. Acad. Sci. USA, 2002, 99, 16742–16747PubMedGoogle Scholar
  90. [90]
    Petkova A.T., Yau W.M., Tycko R., Experimental constraints on quaternary structure in Alzheimer’s β-amyloid fibrils, Biochemistry, 2006, 45, 498–512PubMedCentralPubMedGoogle Scholar
  91. [91]
    Lazo N.D., Grant M.A., Condron M.C., Rigby A.C., Teplow D.B., On the nucleation of amyloid β-protein monomer folding, Protein Sci., 2005, 14, 1581–1596PubMedGoogle Scholar
  92. [92]
    Yu L., Edalji R., Harlan J.E., Holzman T.F., Lopez A.P., Labkovsky B., et al., Structural characterization of a soluble amyloid β-peptide oligomer, Biochemistry, 2009, 48, 1870–1877PubMedGoogle Scholar
  93. [93]
    Wang S.H., Liu F.F., Dong X.Y., Sun Y., Thermodynamic analysis of the molecular interactions between amyloid β-peptide 42 and (−)-epigallocatechin-3-gallate, J. Phys. Chem. B, 2010, 114, 11576–11583PubMedGoogle Scholar
  94. [94]
    Wang S.H., Dong X.Y., Sun Y., Thermodynamic analysis of the molecular interactions between amyloid β-protein fragments and (−)-epigallocatechin-3-gallate, J. Phys. Chem. B, 2012, 116, 5803–5809PubMedGoogle Scholar
  95. [95]
    Hane F., Tran G., Attwood S.J., Leonenko Z., Cu2+ affects amyloid-β (1–42) aggregation by increasing peptide-peptide binding forces, PLoS One, 2013, 8, e59005PubMedCentralPubMedGoogle Scholar
  96. [96]
    Solomonov I., Korkotian E., Born B., Feldman Y., Bitler A., Rahimi F., et al., Zn2+-Aβ40 complexes form metastable quasi-spherical oligomers that are cytotoxic to cultured hippocampal neurons, J. Biol. Chem., 2012, 287, 20555–20564PubMedGoogle Scholar
  97. [97]
    Mancino A.M., Hindo S.S., Kochi A., Lim M.H., Effects of clioquinol on metal-triggered amyloid-β aggregation revisited, Inorg. Chem., 2009, 48, 9596–9598PubMedGoogle Scholar
  98. [98]
    Bush A.I., Masters C.L., Tanzi R.E., Copper, β-amyloid, and Alzheimer’s disease: Tapping a sensitive connection, Proc. Natl. Acad. Sci. USA, 2003, 100, 11193–11194PubMedGoogle Scholar
  99. [99]
    Huang X., Moir R.D., Tanzi R.E., Bush A.I., Rogers J.T., Redox-active metals, oxidative stress, and Alzheimer’s disease pathology, Ann. N. Y. Acad. Sci., 2004, 1012, 153–163PubMedGoogle Scholar
  100. [100]
    Pirker K.F., Baratto M.C., Basosi R., Goodman B.A., Influence of pH on the speciation of copper(II) in reactions with the green tea polyphenols, epigallocatechin gallate and gallic acid, J. Inorg. Biochem., 2012, 112, 10–16PubMedCentralPubMedGoogle Scholar
  101. [101]
    Sun S.L., He G.Q., Yu H.N., Yang J.G., Borthakur D., Zhang L.C., et al., Free Zn2+ enhances inhibitory effects of EGCG on the growth of PC-3 cells, Mol. Nutr. Food Res., 2008, 52, 465–471PubMedGoogle Scholar
  102. [102]
    Weinreb O., Amit T., Mandel S., Youdim M.B., Neuroprotective molecular mechanisms of (−)-epigallocatechin-3-gallate: a reflective outcome of its antioxidant, iron chelating and neuritogenic properties, Genes Nutr. 2009, 4, 283–296PubMedCentralPubMedGoogle Scholar
  103. [103]
    Seeram N.P., Henning S.M., Niu Y., Lee R., Scheuller H.S., Heber D., Catechin and caffeine content of green tea dietary supplements and correlation with antioxidant capacity, J. Agric. Food Chem., 2006, 54, 1599–1603PubMedGoogle Scholar
  104. [104]
    Zhang Y., Jiang T., Zheng Y., Zhou P., Interference of EGCG on the Zn(II)-induced conformational transition of silk fibroin as a model protein related to neurodegenerative diseases, Soft Matter, 2012, 8, 5543–5549Google Scholar
  105. [105]
    Cheng X.R., Hau B.Y., Veloso A.J., Martic S., Kraatz H.B., Kerman K., Surface plasmon resonance imaging of amyloid-β aggregation kinetics in the presence of epigallocatechin gallate and metals, Anal. Chem., 2013, 85, 2049–2055PubMedGoogle Scholar
  106. [106]
    Hyung S.J., DeToma A.S., Brender J.R., Lee S., Vivekanandan S., Kochi A., et al., Insights into antiamyloidogenic properties of the green tea extract (−)-epigallocatechin-3-gallate toward metal-associated amyloid-β species, Proc. Natl. Acad. Sci. USA, 2013, 110, 3743–3748PubMedGoogle Scholar
  107. [107]
    Sinha S., Du Z., Maiti P., Klärner F.G., Schrader T., Wang C., et al., Comparison of three amyloid assembly inhibitors: the sugar scylloinositol, the polyphenol epigallocatechin gallate, and the molecular tweezer CLR01, ACS Chem. Neurosci., 2012, 3, 451–458PubMedGoogle Scholar
  108. [108]
    Miyai S., Yamaguchi A., Iwasaki T., Shamsa F., Ohtsuki K., Biochemical characterization of epigallocatechin-3-gallate as an effective stimulator for the phosphorylation of its binding proteins by glycogen synthase kinase-3β in vitro, Biol. Pharm. Bull., 2010, 33, 1932–1937PubMedGoogle Scholar
  109. [109]
    Takashima A., The Mechanism of tau aggregation and its relation to neuronal dysfunction, Alzheimer’s Association Interantional Conference on Alzheimer’s disease, 2010, S144, Abstract No. PL-104-103.Google Scholar
  110. [110]
    Frost B., Ollesch J., Wille H., Diamond M.I., Conformational diversity of wild-type Tau fibrils specified by templated conformation change, J. Biol. Chem., 2009, 284, 3546–3551PubMedGoogle Scholar
  111. [111]
    Hsiao K., Chapman P., Nilsen S., Eckman C., Harigaya Y., Younkin S., et al., Correlative memory deficits, Aβ elevation, and amyloid plaques in transgenic mice, Science, 1996, 274, 99–102Google Scholar
  112. [112]
    Rezai-Zadeh K., Shytle D., Sun N., Mori T., Hou H., Jeanniton D., et al., Green tea epigallocatechin-3-gallate (EGCG) modulates amyloid precursor protein cleavage and reduces cerebral amyloidosis in Alzheimer transgenic mice, J. Neurosci., 2005, 25, 8807–8814PubMedGoogle Scholar
  113. [113]
    Rezai-Zadeh K., Arendash G.W., Hou H., Fernandez F., Jensen M., Runfeldt M., et al., Green tea epigallocatechin-3-gallate (EGCG) reduces β-amyloid mediated cognitive impairment and modulates tau pathology in Alzheimer transgenic mice, Brain Res., 2008, 1214, 177–187PubMedGoogle Scholar
  114. [114]
    Hwang D.Y., Chae K.R., Kang T.S., Hwang J.H., Lim C.H., Kang H.K., et al., Alterations in behavior, amyloid β-42, caspase-3, and Cox-2 in mutant PS2 transgenic mouse model of Alzheimer’s disease, FASEB J., 2002, 16, 805–813PubMedGoogle Scholar
  115. [115]
    Lee J.W., Lee Y.K., Ban J.O., Ha T.Y., Yun Y.P., Han S.B., et al., Green tea (−)-epigallocatechin-3-gallate inhibits β-amyloid-induced cognitive dysfunction through modification of secretase activity via inhibition of ERK and NF-κB pathways in mice, J. Nutr., 2009, 139, 1987–1993PubMedGoogle Scholar
  116. [116]
    Lee S.Y., Lee J.W., Lee H., Yoo H.S., Yun Y.P., Oh K.W., et al., Inhibitory effect of green tea extract on β-amyloid-induced PC12 cell death by inhibition of the activation of NF-κB and ERK/p38 MAP kinase pathway through antioxidant mechanisms, Brain Res. Mol. Brain Res., 2005, 140, 45–54PubMedGoogle Scholar
  117. [117]
    Rasoolijazi H., Joghataie M.T., Roghani M., Nobakht M., The beneficial effect of (−)-epigallocatechin-3-gallate in an experimental model of Alzheimer’s disease in rat: a behavioral analysis, Iran Biomed. J., 2007, 11, 237–243PubMedGoogle Scholar
  118. [118]
    Lee Y.K., Yuk D.Y., Lee J.W., Lee S.Y., Ha T.Y., Oh K.W., et al., (−)-Epigallocatechin-3-gallate prevents lipopolysaccharide-induced elevation of β-amyloid generation and memory deficiency, Brain Res., 2009, 1250, 164–174PubMedGoogle Scholar
  119. [119]
    Lee Y.J., Choi D.Y., Yun Y.P., Han S.B., Oh K.W., Hong J.T., Epigallocatechin-3-gallate prevents systemic inflammationinduced memory deficiency and amyloidogenesis via its antineuroinflammatory properties, J. Nutr. Biochem., 2013, 24, 298–310PubMedGoogle Scholar
  120. [120]
    Miklossy J., Kis A., Radenovic A., Miller L., Forro L., Martins R., et al., β-amyloid deposition and Alzheimer’s type changes induced by Borrelia spirochetes, Neurobiol. Aging, 2006, 27, 228–236PubMedGoogle Scholar
  121. [121]
    Link C.D., Expression of human β-amyloid peptide in transgenic Caenorhabditis elegans, Proc. Natl. Acad. Sci. USA, 1995, 92, 9368–9372PubMedGoogle Scholar
  122. [122]
    Abbas S., Wink M., Epigallocatechin gallate inhibits β amyloid oligomerization in Caenorhabditis elegans and affects the daf-2/ insulin-like signaling pathway, Phytomedicine, 2010, 17, 902–909PubMedGoogle Scholar
  123. [123]
    Bitan G., Fradinger E.A., Spring S.M., Teplow D.B., Neurotoxic protein oligomers—what you see is not always what you get, Amyloid, 2005, 12, 88–95PubMedGoogle Scholar
  124. [124]
    Hepler R.W., Grimm K.M., Nahas D.D., Breese R., Dodson E.C., Acton P., et al., Solution state characterization of amyloid β-derived diffusible ligands, Biochemistry, 2006, 45, 15157–15167PubMedGoogle Scholar
  125. [125]
    Khan J.M., Qadeer A., Chaturvedi S.K., Ahmad E., Rehman S.A., Gourinath S., et al., SDS can be utilized as an amyloid inducer: a case study on diverse proteins, PLoS One, 2012, 7, e29694PubMedCentralPubMedGoogle Scholar
  126. [126]
    Watt A.D., Perez K.A., Rembach A., Sherrat N.A., Hung L.W., Johanssen T., et al., Oligomers, fact or artefact? SDS-PAGE induces dimerization of β-amyloid in human brain samples, Acta Neuropathol. (Berl). 2013Google Scholar
  127. [127]
    Jankowsky J.L., Fadale D.J., Anderson J., Xu G.M., Gonzales V., Jenkins N.A., et al., Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase, Hum. Mol. Genet., 2004, 13, 159–170PubMedGoogle Scholar
  128. [128]
    Oddo S., Caccamo A., Shepherd J.D., Murphy M.P., Golde T.E., Kayed R., et al., Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction, Neuron, 2003, 39, 409–421PubMedGoogle Scholar
  129. [129]
    George J.M., Jin H., Woods W.S., Clayton D.F., Characterization of a novel protein regulated during the critical period for song learning in the zebra finch, Neuron, 1995, 15, 361–372PubMedGoogle Scholar
  130. [130]
    Maroteaux L., Scheller R.H., The rat brain synucleins; family of proteins transiently associated with neuronal membrane, Brain Res. Mol. Brain Res., 1991, 11, 335–343PubMedGoogle Scholar
  131. [131]
    Maroteaux L., Campanelli J.T., Scheller R.H., Synuclein: a neuronspecific protein localized to the nucleus and presynaptic nerve terminal, J. Neurosci., 1988, 8, 2804–2815PubMedGoogle Scholar
  132. [132]
    Bendor J.T., Logan T.P., Edwards R.H., The function of α-synuclein, Neuron, 2013, 79, 1044–1066PubMedGoogle Scholar
  133. [133]
    El-Agnaf O.M.A., Jakes R., Curran M.D., Middleton D., Ingenito R., Bianchi E., et al., Aggregates from mutant and wild-type α-synuclein proteins and NAC peptide induce apoptotic cell death in human neuroblastoma cells by formation of β-sheet and amyloid-like filaments, FEBS Lett., 1998, 440, 71–75PubMedGoogle Scholar
  134. [134]
    Acharya S., Safaie B., Wongkongkathep P., Ivanova M.I., Attar A., Klärner F.-G., et al., Molecular basis for preventing α-synuclein aggregation by a molecular tweezer, 2013, Submitted for publicationGoogle Scholar
  135. [135]
    Ng C.H., Mok S.Z., Koh C., Ouyang X., Fivaz M.L., Tan E.K., et al., Parkin protects against LRRK2 G2019S mutant-induced dopaminergic neurodegeneration in Drosophila, J. Neurosci., 2009, 29, 11257–11262PubMedCentralPubMedGoogle Scholar
  136. [136]
    Wang C., Lu R., Ouyang X., Ho M.W., Chia W., Yu F., et al., Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities, J. Neurosci., 2007, 27, 8563–8570PubMedGoogle Scholar
  137. [137]
    Ng C.H., Guan M.S., Koh C., Ouyang X., Yu F., Tan E.K., et al., AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson’s disease, J. Neurosci., 2012, 32, 14311–14317PubMedGoogle Scholar
  138. [138]
    Bonilla-Ramirez L., Jimenez-Del-Rio M., Velez-Pardo C., Low doses of paraquat and polyphenols prolong life span and locomotor activity in knock-down parkin Drosophila melanogaster exposed to oxidative stress stimuli: implication in autosomal recessive juvenile Parkinsonism, Gene, 2013, 512, 355–363PubMedGoogle Scholar
  139. [139]
    Choi J.Y., Park C.S., Kim D.J., Cho M.H., Jin B.K., Pie J.E., et al., Prevention of nitric oxide-mediated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineinduced Parkinson’s disease in mice by tea phenolic epigallocatechin 3-gallate, Neurotoxicology, 2002, 23, 367–374PubMedGoogle Scholar
  140. [140]
    Kim J.S., Kim J.M., O J.J., Jeon B.S., Inhibition of inducible nitric oxide synthase expression and cell death by (−)-epigallocatechin-3-gallate, a green tea catechin, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson’s disease, J. Clin. Neurosci., 2010, 17, 1165–1168PubMedGoogle Scholar
  141. [141]
    Reznichenko L., Kalfon L., Amit T., Youdim M.B., Mandel S.A., Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism, Neurodegener. Dis., 2010, 7, 219–231PubMedGoogle Scholar
  142. [142]
    Youdim M.B., Grunblatt E., Levites Y., Maor G., Mandel S., Early and late molecular events in neurodegeneration and neuroprotection in Parkinson’s disease MPTP model as assessed by cDNA microarray; the role of iron, Neurotox. Res., 2002, 4, 679–689PubMedGoogle Scholar
  143. [143]
    Leaver K.R., Allbutt H.N., Creber N.J., Kassiou M., Henderson J.M., Oral pre-treatment with epigallocatechin gallate in 6-OHDA lesioned rats produces subtle symptomatic relief but not neuroprotection, Brain Res. Bull., 2009, 80, 397–402PubMedGoogle Scholar
  144. [144]
    Kang K.S., Wen Y., Yamabe N., Fukui M., Bishop S.C., Zhu B.T., Dual beneficial effects of (−)-epigallocatechin-3-gallate on levodopa methylation and hippocampal neurodegeneration: in vitro and in vivo studies, PLoS One, 2010, 5, e11951PubMedCentralPubMedGoogle Scholar
  145. [145]
    Emmanouilidou E., Stefanis L., Vekrellis K., Cell-produced α-synuclein oligomers are targeted to, and impair, the 26S proteasome, Neurobiol. Aging, 2010, 31, 953–968PubMedGoogle Scholar
  146. [146]
    Zhang N.Y., Tang Z., Liu C.W., α-Synuclein protofibrils inhibit 26 S proteasome-mediated protein degradation: understanding the cytotoxicity of protein protofibrils in neurodegenerative disease pathogenesis, J. Biol. Chem., 2008, 283, 20288–20298PubMedGoogle Scholar
  147. [147]
    Lulla A., Barnhill L., Stahl M., Fitzmaurice A.G., Li S., Bronstein J.M., Neurotoxicity of the dithiocarbamate fungicide ziram is dependent on synuclein in zebrafish: Implications for Parkinson’s disease, Society of Toxicology Annual Meeting, 2013, Abstract #1407.Google Scholar
  148. [148]
    Wang X.F., Li S., Chou A.P., Bronstein J.M., Inhibitory effects of pesticides on proteasome activity: implication in Parkinson’s disease, Neurobiol. Dis., 2006, 23, 198–205PubMedGoogle Scholar
  149. [149]
    Zhou Y., Shie F.S., Piccardo P., Montine T.J., Zhang J., Proteasomal inhibition induced by manganese ethylene-bis-dithiocarbamate: relevance to Parkinson’s disease, Neuroscience, 2004, 128, 281–291PubMedGoogle Scholar
  150. [150]
    Chou A.P., Maidment N., Klintenberg R., Casida J.E., Li S., Fitzmaurice A.G., et al., Ziram causes dopaminergic cell damage by inhibiting E1 ligase of the proteasome, J. Biol. Chem., 2008, 283, 34696–34703PubMedGoogle Scholar
  151. [151]
    Wang A., Costello S., Cockburn M., Zhang X., Bronstein J., Ritz B., Parkinson’s disease risk from ambient exposure to pesticides, Eur. J. Epidemiol., 2011, 26, 547–555PubMedCentralPubMedGoogle Scholar
  152. [152]
    Rinetti G.V., Schweizer F.E., Ubiquitination acutely regulates presynaptic neurotransmitter release in mammalian neurons, J. Neurosci., 2010, 30, 3157–3166PubMedCentralPubMedGoogle Scholar
  153. [153]
    Saraiva M., Cardoso I., Transthyretin Aggregation and Toxicity, In: Rahimi F., Bitan G. (Eds.), Non-fibrillar Amyloidogenic Protein Assemblies—Common Cytotoxins Underlying Degenerative Diseases, Springer Netherlands, 2012Google Scholar
  154. [154]
    Westermark P., Senile systemic amyloidosis — An overview, Amyloid, 2001, 8, 121Google Scholar
  155. [155]
    Ferreira N., Cardoso I., Domingues M.R., Vitorino R., Bastos M., Bai G., et al., Binding of epigallocatechin-3-gallate to transthyretin modulates its amyloidogenicity, FEBS Lett., 2009, 583, 3569–3576PubMedGoogle Scholar
  156. [156]
    Miyata M., Sato T., Kugimiya M., Sho M., Nakamura T., Ikemizu S., et al., The crystal structure of the green tea polyphenol (−)-epigallocatechin gallate-transthyretin complex reveals a novel binding site distinct from the thyroxine binding site, Biochemistry, 2010, 49, 6104–6114PubMedGoogle Scholar
  157. [157]
    Kristen A.V., Lehrke S., Buss S., Mereles D., Steen H., Ehlermann P., et al., Green tea halts progression of cardiac transthyretin amyloidosis: an observational report, Clin. Res. Cardiol., 2012, 101, 805–813PubMedCentralPubMedGoogle Scholar
  158. [158]
    Kristen A.V., Perz J.B., Schonland S.O., Hegenbart U., Schnabel P.A., Kristen J.H., et al., Non-invasive predictors of survival in cardiac amyloidosis, Eur. J. Heart Fail., 2007, 9, 617–624PubMedGoogle Scholar
  159. [159]
    Mörner S., Hellman U., Suhr O.B., Kazzam E., Waldenstrom A., Amyloid heart disease mimicking hypertrophic cardiomyopathy, J. Intern. Med., 2005, 258, 225–230PubMedGoogle Scholar
  160. [160]
    Ferreira N., Saraiva M.J., Almeida M.R., Epigallocatechin-3-gallate as a potential therapeutic drug for TTR-related amyloidosis: “in vivo” evidence from FAP mice models, PLoS One, 2012, 7, e29933PubMedCentralPubMedGoogle Scholar
  161. [161]
    Santos S.D., Fernandes R., Saraiva M.J., The heat shock response modulates transthyretin deposition in the peripheral and autonomic nervous systems, Neurobiol. Aging, 2010, 31, 280–289PubMedGoogle Scholar
  162. [162]
    Ferreira N., Pereira-Henriques A., Attar A., Klärner F.-G., Schrader T., Bitan G., et al., Molecular Tweezers Targeting Transthyretin Amyloidosis, 2013, Submitted for publicationGoogle Scholar
  163. [163]
    Westermark P., Wernstedt C., Wilander E., Hayden D.W., O’Brien T.D., Johnson K.H., Amyloid fibrils in human insulinoma and islets of Langerhans of the diabetic cat are derived from a neuropeptide-like protein also present in normal islet cells, Proc. Natl. Acad. Sci. USA, 1987, 84, 3881–3885PubMedGoogle Scholar
  164. [164]
    Cooper G.J., Willis A.C., Clark A., Turner R.C., Sim R.B., Reid K.B., Purification and characterization of a peptide from amyloid-rich pancreases of type 2 diabetic patients, Proc. Natl. Acad. Sci. USA, 1987, 84, 8628–8632PubMedGoogle Scholar
  165. [165]
    Kahn S.E., Andrikopoulos S., Verchere C.B., Islet amyloid: a longrecognized but underappreciated pathological feature of type 2 diabetes, Diabetes, 1999, 48, 241–253PubMedGoogle Scholar
  166. [166]
    Clark A., Cooper G.J., Lewis C.E., Morris J.F., Willis A.C., Reid K.B., et al., Islet amyloid formed from diabetes-associated peptide may be pathogenic in type-2 diabetes, Lancet, 1987, 2, 231–234PubMedGoogle Scholar
  167. [167]
    Hull R.L., Westermark G.T., Westermark P., Kahn S.E., Islet amyloid: a critical entity in the pathogenesis of type 2 diabetes, J. Clin. Endocrinol. Metab., 2004, 89, 3629–3643PubMedGoogle Scholar
  168. [168]
    Lorenzo A., Razzaboni B., Weir G.C., Yankner B.A., Pancreatic islet cell toxicity of amylin associated with type-2 diabetes mellitus, Nature, 1994, 368, 756–760PubMedGoogle Scholar
  169. [169]
    Clark A., Wells C.A., Buley I.D., Cruickshank J.K., Vanhegan R.I., Matthews D.R., et al., Islet amyloid, increased a-cells, reduced b-cells and exocrine fibrosis: quantitative changes in the pancreas in type 2 diabetes, Diabetes Res., 1988, 9, 151–159PubMedGoogle Scholar
  170. [170]
    Butler A.E., Janson J., Bonner-Weir S., Ritzel R., Rizza R.A., Butler P.C., β-Cell deficit and increased β-cell apoptosis in humans with type 2 diabetes, Diabetes, 2003, 52, 102–110PubMedGoogle Scholar
  171. [171]
    Bahramikia S., Yazdanparast R., Inhibition of human islet amyloid polypeptide or amylin aggregation by two manganese-salen derivatives, Eur. J. Pharmacol., 2013, 707, 17–25PubMedGoogle Scholar
  172. [172]
    Cheng B., Gong H., Li X., Sun Y., Chen H., Zhang X., et al., Salvianolic acid B inhibits the amyloid formation of human islet amyloid polypeptideand protects pancreatic β-cells against cytotoxicity, Proteins, 2013, 81, 613–621PubMedGoogle Scholar
  173. [173]
    Cheng B., Gong H., Li X., Sun Y., Zhang X., Chen H., et al., Silibinin inhibits the toxic aggregation of human islet amyloid polypeptide, Biochem. Biophys. Res. Commun., 2012, 419, 495–499PubMedGoogle Scholar
  174. [174]
    Hagihara M., Takei A., Ishii T., Hayashi F., Kubota K., Wakamatsu K., et al., Inhibitory effects of choline-O-sulfate on amyloid formation of human islet amyloid polypeptide, FEBS open bio, 2012, 2, 20–25PubMedCentralPubMedGoogle Scholar
  175. [175]
    Seeliger J., Winter R., Islet amyloid polypeptide: Aggregation and fibrillogenesis in vitro and its inhibition, Subcell. Biochem., 2012, 65, 185–209PubMedGoogle Scholar
  176. [176]
    Engel M.F., vandenAkker C.C., Schleeger M., Velikov K.P., Koenderink G.H., Bonn M., The polyphenol EGCG inhibits amyloid formation less efficiently at phospholipid interfaces than in bulk solution, J. Am. Chem. Soc., 2012, 134, 14781–14788PubMedGoogle Scholar
  177. [177]
    Fu L., Ma G., Yan E.C., In situ misfolding of human islet amyloid polypeptide at interfaces probed by vibrational sum frequency generation, J. Am. Chem. Soc., 2010, 132, 5405–5412PubMedGoogle Scholar
  178. [178]
    Fu L., Liu J., Yan E.C., Chiral sum frequency generation spectroscopy for characterizing protein secondary structures at interfaces, J. Am. Chem. Soc., 2011, 133, 8094–8097PubMedGoogle Scholar
  179. [179]
    Suzuki Y., Brender J.R., Hartman K., Ramamoorthy A., Marsh E.N., Alternative pathways of human islet amyloid polypeptide aggregation distinguished by 19F nuclear magnetic resonancedetected kinetics of monomer consumption, Biochemistry, 2012, 51, 8154–8162PubMedCentralPubMedGoogle Scholar
  180. [180]
    Lopes D.H.J., Attar A., Du Z., McDaniel K., Dutt S., Bravo-Rodriguez K., et al., The molecular tweezer CLR01 inhibits islet amyloid polypeptide assembly and toxicity via an unexpected mechanism, 2013, Submitted for publicationGoogle Scholar
  181. [181]
    Sexton P.M., Findlay D.M., Martin T.J., Calcitonin, Curr. Med. Chem., 1999, 6, 1067–1093PubMedGoogle Scholar
  182. [182]
    Copp D.H., Calcitonin: discovery, development, and clinical application, Clin. Invest. Med., 1994, 17, 268–277PubMedGoogle Scholar
  183. [183]
    Huang C.L., Sun L., Moonga B.S., Zaidi M., Molecular physiology and pharmacology of calcitonin, Cellular and molecular biology (Noisyle-Grand, France), 2006, 52, 33–43Google Scholar
  184. [184]
    Foster G.V., Calcitonin (thyrocalcitonin), N. Engl. J. Med., 1968, 279, 349–360PubMedGoogle Scholar
  185. [185]
    Haymovits A., Rosen J.F., Calcitonin in metabolic disorders, Adv. Metab. Disord., 1972, 60, 177–212PubMedGoogle Scholar
  186. [186]
    Huang R., Vivekanandan S., Brender J.R., Abe Y., Naito A., Ramamoorthy A., NMR characterization of monomeric and oligomeric conformations of human calcitonin and its interaction with EGCG, J. Mol. Biol., 2012, 416, 108–120PubMedCentralPubMedGoogle Scholar
  187. [187]
    Molinari M., Watt K.D., Kruszyna T., Nelson R., Walsh M., Huang W.Y., et al., Acute liver failure induced by green tea extracts: case report and review of the literature, Liver Transpl., 2006, 12, 1892–1895PubMedGoogle Scholar
  188. [188]
    Isbrucker R.A., Bausch J., Edwards J.A., Wolz E., Safety studies on epigallocatechin gallate (EGCG) preparations. Part 1: genotoxicity, Food Chem. Toxicol., 2006, 44, 626–635PubMedGoogle Scholar
  189. [189]
    Isbrucker R.A., Edwards J.A., Wolz E., Davidovich A., Bausch J., Safety studies on epigallocatechin gallate (EGCG) preparations. Part 3: teratogenicity and reproductive toxicity studies in rats, Food Chem. Toxicol., 2006, 44, 651–661PubMedGoogle Scholar
  190. [190]
    Isbrucker R.A., Edwards J.A., Wolz E., Davidovich A., Bausch J., Safety studies on epigallocatechin gallate (EGCG) preparations. Part 2: dermal, acute and short-term toxicity studies, Food Chem. Toxicol., 2006, 44, 636–650PubMedGoogle Scholar
  191. [191]
    Lambert J.D., Kennett M.J., Sang S., Reuhl K.R., Ju J., Yang C.S., Hepatotoxicity of high oral dose (−)-epigallocatechin-3-gallate in mice, Food Chem. Toxicol., 2010, 48, 409–416PubMedCentralPubMedGoogle Scholar
  192. [192]
    Goodin M.G., Rosengren R.J., Epigallocatechin gallate modulates CYP450 isoforms in the female Swiss-Webster mouse, Toxicol. Sci., 2003, 76, 262–270PubMedGoogle Scholar
  193. [193]
    Kapetanovic I.M., Crowell J.A., Krishnaraj R., Zakharov A., Lindeblad M., Lyubimov A., Exposure and toxicity of green tea polyphenols in fasted and non-fasted dogs, Toxicology, 2009, 260, 28–36PubMedCentralPubMedGoogle Scholar
  194. [194]
    Guengerich F.P., Cytochrome p450 and chemical toxicology, Chem. Res. Toxicol., 2008, 21, 70–83PubMedGoogle Scholar
  195. [195]
    Huynh H.T., Teel R.W., Effects of plant-derived phenols on rat liver cytochrome P450 2B1 activity, Anticancer Res., 2002, 22, 1699–1703PubMedGoogle Scholar
  196. [196]
    Ullmann U., Haller J., Decourt J.P., Girault N., Girault J., Richard-Caudron A.S., et al., A single ascending dose study of epigallocatechin gallate in healthy volunteers, J. Int. Med. Res., 2003, 31, 88–101PubMedGoogle Scholar
  197. [197]
    Chow H.H., Hakim I.A., Vining D.R., Crowell J.A., Ranger-Moore J., Chew W.M., et al., Effects of dosing condition on the oral bioavailability of green tea catechins after single-dose administration of Polyphenon E in healthy individuals, Clin. Cancer Res., 2005, 11, 4627–4633PubMedGoogle Scholar
  198. [198]
    Ullmann U., Haller J., Decourt J.D., Girault J., Spitzer V., Weber P., Plasma-kinetic characteristics of purified and isolated green tea catechin epigallocatechin gallate (EGCG) after 10 days repeated dosing in healthy volunteers, International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Int. J. Vitam. Nutr. Res., 2004, 74, 269–278Google Scholar
  199. [199]
    Chow H.H., Cai Y., Hakim I.A., Crowell J.A., Shahi F., Brooks C.A., et al., Pharmacokinetics and safety of green tea polyphenols after multipledose administration of epigallocatechin gallate and polyphenon E in healthy individuals, Clin. Cancer Res., 2003, 9, 3312–3319PubMedGoogle Scholar
  200. [200]
    Hsu C.H., Liao Y.L., Lin S.C., Tsai T.H., Huang C.J., Chou P., Does supplementation with green tea extract improve insulin resistance in obese type 2 diabetics? A randomized, double-blind, and placebocontrolled clinical trial, Altern. Med. Rev., 2011, 16, 157–163PubMedGoogle Scholar
  201. [201]
    Jimenez-Saenz M., Martinez-Sanchez Mdel C., Acute hepatitis associated with the use of green tea infusions, J. Hepatol., 2006, 44, 616–617PubMedGoogle Scholar
  202. [202]
    Crew K.D., Brown P., Greenlee H., Bevers T.B., Arun B., Hudis C., et al., Phase IB randomized, double-blinded, placebo-controlled, dose escalation study of polyphenon E in women with hormone receptor-negative breast cancer, Cancer Prev. Res., 2012, 5, 1144–1154Google Scholar
  203. [203]
    Bonkovsky H.L., Hepatotoxicity associated with supplements containing Chinese green tea (Camellia sinensis), Ann. Intern. Med., 2006, 144, 68–71PubMedGoogle Scholar
  204. [204]
    Mazzanti G., Menniti-Ippolito F., Moro P.A., Cassetti F., Raschetti R., Santuccio C., et al., Hepatotoxicity from green tea: a review of the literature and two unpublished cases, Eur. J. Clin. Pharmacol., 2009, 65, 331–341PubMedGoogle Scholar
  205. [205]
    Attar A., Chan W.-T.C., Klärner F.-G., Schrader T., Bitan G., Safety and pharmacokinetic characterization of the molecular tweezer CLR01 in vivo, 2013, Manuscript in preparationGoogle Scholar
  206. [206]
    Obach R.S., Walsky R.L., Venkatakrishnan K., Gaman E.A., Houston J.B., Tremaine L.M., The utility of in vitro cytochrome P450 inhibition data in the prediction of drug-drug interactions, J. Pharmacol. Exp. Ther., 2006, 316, 336–348PubMedGoogle Scholar
  207. [207]
    Williamson G., Dionisi F., Renouf M., Flavanols from green tea and phenolic acids from coffee: critical quantitative evaluation of the pharmacokinetic data in humans after consumption of single doses of beverages, Mol. Nutr. Food Res., 2011, 55, 864–873PubMedGoogle Scholar
  208. [208]
    Yang C.S., Chen L., Lee M.J., Balentine D., Kuo M.C., Schantz S.P., Blood and urine levels of tea catechins after ingestion of different amounts of green tea by human volunteers, Cancer Epidemiol. Biomarkers Prev., 1998, 7, 351–354PubMedGoogle Scholar
  209. [209]
    Chow H.H., Cai Y., Alberts D.S., Hakim I., Dorr R., Shahi F., et al., Phase I pharmacokinetic study of tea polyphenols following single-dose administration of epigallocatechin gallate and polyphenon E, Cancer Epidemiol. Biomarkers Prev., 2001, 10, 53–58PubMedGoogle Scholar
  210. [210]
    Renouf M., Guy P., Marmet C., Longet K., Fraering A.L., Moulin J., et al., Plasma appearance and correlation between coffee and green tea metabolites in human subjects, Br. J. Nutr., 2010, 104, 1635–1640PubMedGoogle Scholar
  211. [211]
    Van Amelsvoort J.M., Van Hof K.H., Mathot J.N., Mulder T.P., Wiersma A., Tijburg L.B., Plasma concentrations of individual tea catechins after a single oral dose in humans, Xenobiotica, 2001, 31, 891–901PubMedGoogle Scholar
  212. [212]
    Lee M.J., Wang Z.Y., Li H., Chen L., Sun Y., Gobbo S., et al., Analysis of plasma and urinary tea polyphenols in human subjects, Cancer Epidemiol. Biomarkers Prev., 1995, 4, 393–399PubMedGoogle Scholar
  213. [213]
    Mateos R., Goya L., Bravo L., Uptake and metabolism of hydroxycinnamic acids (chlorogenic, caffeic, and ferulic acids) by HepG2 cells as a model of the human liver, J. Agric. Food Chem., 2006, 54, 8724–8732PubMedGoogle Scholar
  214. [214]
    Meng X., Sang S., Zhu N., Lu H., Sheng S., Lee M.J., et al., Identification and characterization of methylated and ring-fission metabolites of tea catechins formed in humans, mice, and rats, Chem. Res. Toxicol., 2002, 15, 1042–1050PubMedGoogle Scholar
  215. [215]
    Walle T., Methylation of dietary flavones greatly improves their hepatic metabolic stability and intestinal absorption, Mol. Pharm., 2007, 4, 826–832PubMedGoogle Scholar
  216. [216]
    Maeda-Yamamoto M., Ema K., Monobe M., Tokuda Y., Tachibana H., Epicatechin-3-O-(3″-O-methyl)-gallate content in various tea cultivars (Camellia sinensis L.) and its in vitro inhibitory effect on histamine release, J. Agric. Food Chem., 2012, 60, 2165–2170PubMedGoogle Scholar
  217. [217]
    Harada M., Kan Y., Naoki H., Fukui Y., Kageyama N., Nakai M., et al., Identification of the major antioxidative metabolites in biological fluids of the rat with ingested (+)-catechin and (−)-epicatechin, Biosci. Biotechnol. Biochem., 1999, 63, 973–977PubMedGoogle Scholar
  218. [218]
    Giunta B., Hou H., Zhu Y., Salemi J., Ruscin A., Shytle R.D., et al., Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice, Neurosci. Lett., 2010, 471, 134–138PubMedGoogle Scholar
  219. [219]
    Sang S., Lee M.J., Hou Z., Ho C.T., Yang C.S., Stability of tea polyphenol (−)-epigallocatechin-3-gallate and formation of dimers and epimers under common experimental conditions, J. Agric. Food Chem., 2005, 53, 9478–9484PubMedGoogle Scholar
  220. [220]
    Ishii T., Mori T., Tanaka T., Mizuno D., Yamaji R., Kumazawa S., et al., Covalent modification of proteins by green tea polyphenol (−)-epigallocatechin-3-gallate through autoxidation, Free Radic. Biol. Med., 2008, 45, 1384–1394PubMedGoogle Scholar
  221. [221]
    Sato M., Murakami K., Uno M., Nakagawa Y., Katayama S., Akagi K.I., et al., Site-specific inhibitory mechanism for amyloid-β42 aggregation by catechol-type flavonoids targeting the Lys residues, J. Biol. Chem., 2013Google Scholar
  222. [222]
    Okada K., Wangpoengtrakul C., Osawa T., Toyokuni S., Tanaka K., Uchida K., 4-hydroxy-2-nonenal-mediated impairment of intracellular proteolysis during oxidative stress — Identification of proteasomes as target molecules, J. Biol. Chem., 1999, 274, 23787–23793PubMedGoogle Scholar
  223. [223]
    Qin Z., Hu D., Han S., Reaney S.H., Di Monte D.A., Fink A.L., Effect of 4-hydroxy-2-nonenal modification on α-synuclein aggregation, J. Biol. Chem., 2007, 282, 5862–5870PubMedGoogle Scholar
  224. [224]
    Perez M., Cuadros R., Smith M.A., Perry G., Avila J., Phosphorylated, but not native, tau protein assembles following reaction with the lipid peroxidation product, 4-hydroxy-2-nonenal, FEBS Lett., 2000, 486, 270–274PubMedGoogle Scholar

Copyright information

© Versita Warsaw and Springer-Verlag Wien 2013

Authors and Affiliations

  1. 1.Department of Neurology, David Geffen School of MedicineUniversity of California at Los AngelesLos AngelesUSA
  2. 2.Brain Research InstituteUniversity of California at Los AngelesLos AngelesUSA
  3. 3.Molecular Biology InstituteUniversity of California at Los AngelesLos AngelesUSA
  4. 4.Research School of Biology, College of Medicine, Biology, and EnvironmentThe Australian National UniversityCanberraAustralia

Personalised recommendations